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1 Introduction of Clinical Trials Jessie Zhou Dept.of Clinical Epidemiology and Biostatistics McMaster University August 1, 2011.

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Presentation on theme: "1 Introduction of Clinical Trials Jessie Zhou Dept.of Clinical Epidemiology and Biostatistics McMaster University August 1, 2011."— Presentation transcript:

1 1 Introduction of Clinical Trials Jessie Zhou Dept.of Clinical Epidemiology and Biostatistics McMaster University August 1, 2011

2 Outline Overview of clinical trials History of the clinical trials Types of the clinical trials Design of the clinical trials Phases of the clinical trials Some issues on clinical trials design 2

3 3 Overview of Clinical Trials What is Clinical Trials Any form of planned experiment which involves patients and is designed to answer scientific questions and find better ways to prevent, diagnose, or treat disease. To discover or verify: To discover or verify: – Pharmaco dynamics (how it works) – Pharmacokinetics (what happens to it) – Therapeutic effects (Efficacy) – Adverse reactions (Safety)

4 4 Overview of Clinical Trials

5 5 General thoughts: – Study must examine valuable and important biomedical research questions. – It must be based on rigorous methodology & It must follow strong ethical principles. –The probability and magnitude of risk – benefit to the participants. –The population to be studied – its Size, Availability and Accessibility.

6 6 Overview of Clinical Trials Some examples: –Assess the safety and effectiveness of a new medication or device on a specific kind of patient (e.g., patients who have been diagnosed with Alzheimer's disease) Alzheimer's disease –Assess the safety and effectiveness of a different dose of a medication than is commonly used (e.g., 10 mg dose instead of 5 mg dose) –Assess whether the new medication or device is more effective for the patient's condition than the already used, standard medication or device ("the gold standard" or "standard therapy“)

7 7 History of Clinical Trials The history of clinical trials before 1750 is brief –The first reference - King Nebuchadnezzar II –Persian scientist Ibn Sina wrote Canon of Medicine around the 10 th century One of the most famous clinical trials was James Lind's demonstration in 1747 that citrus fruits cure scurvyJames Lindcitrus fruitsscurvy Frederick Akbar Mahomed (1884), made substantial contributions to the process of clinical trialsFrederick Akbar Mahomed –separated chronic nephritis with secondary hypertension from what we now term essential hypertensionnephritissecondary hypertensionessential hypertension –founded "the Collective Investigation Record for the British Medical Association British Medical Association

8 8 History of Clinical Trials From 1800 onwards, more attention was paid to study design. – Placebos were first used in –The idea of randomization was introduced in 1923 –In 1930, the US Food and Drug Administration (FDA) was found. –The first trial using properly randomized treatment and control groups was carried out in 1948 –Since 1945, the ethical impact of clinical trials has become increasingly important –Clinical trials have thus evolved into a standard procedure, focusing on patient safety and requiring informed consent from all participants.

9 9 Types of Clinical Trials By type of products –Pharmaceutical Products (Synthetic “Drugs”) –Biotechnology Products (products made from human cells/tissues for example, such as vaccines, blood products) –Devices (e.g., cardiac stents, pacemakers)

10 Types of Clinical Trials By purpose of the trials Treatment trials Prevention trials Early-detection trials/screening trials Diagnostic trials Quality-of-life studies/supportive care studies 10

11 Types of Clinical Trials By the way of research behave –Treatment studies Randomized controlled trial Nonrandomized trial (quasi-experiment) –Observational studies Cohort study Case-control study Cross-sectional study Ecological study 11

12 12 Phases of Clinical Trials Pre-Clinical (in vivo, in vitro) Phase I - Safety & Early Clinical Pharmacology Phase II - Initial Efficacy & Safety. Phase III - Comprehensive Efficacy & Safety Phase IV - Post Marketing surveillance Studies

13 13 Phase I Clinical Trials First time in humans Objectives –Assess pharmacology/pharmacokinetics How drug flows through body How drug is excreted and how long (half-life) –Assess toxicology (safety) Adverse events, Labs, EKGs, Vital Signs, Physical Exams Determine maximum tolderated dose (MTD) –Performed usually in subjects –No interest in efficacy –Descriptive Analysis

14 14 Phase II Clinical Trials Performed in usually patients –Sample often based on time, cost considerations Concentrate on safety, but also look at efficacy Often exploratory in terms of efficacy –Find parameters on which product is efficacious? –Find magnitude of the product’s effect on these parameters? Contains control group (placebo/active)

15 15 Phase II Clinical Trials Multiple doses Find dose with best safety profile and best efficacy profile (not always the highest dose) Use results to design confirmatory Phase III trials –Not necessarily required to obtain statistical significance (“p<0.05”) in Phase II in order to move to Phase III

16 16 Phase III Clinical Trials Objective –Confirm efficacy of new drug seen in Phase II –Determine safety of new drug (especially for uncommon “adverse events”). Often called “Pivotal” trials

17 17 Phase III Clinical Trials Often performed in 2 treatment groups –Study drug vs. Control Control may be Active or Placebo Some suggest both Active and Placebo control If Active-controlled, not necessary to show superiority, but “non-inferiority” or “equivalence” FDA has no official rules about control group

18 18 Phase III Clinical Trials Sample size based heavily on statistics –If treatment works in population, we want a sample large enough to represent population –i.e., Want a high probability treatment works in sample FDA usually requires 2 phase III studies, with p<0.05 for efficacy (if superiority trial) For “large simple trials” only one large study may suffice (with, say, p<0.01 or p<0.001).

19 19 Phase II/III Clinical Trials Phase IIb, Phase II/III Trials –Exploratory, but less so than Phase II –State a specific analysis; if successful, consider study as one of the Phase IIIs (“pivotal”) –If not successful, then consider as exploratory analysis for planning Phase III

20 20 Phase IV Clinical Trials Post Marketing Surveillance Trial –Involve the safety surveillance (pharmacovigilance) and ongoing technical supportpharmacovigilance –Required by regulatory authorities or may be undertaken by the sponsoring company for competitive or other reasons –Detect any rare or long-term adverse effects over a much larger patient population and longer time period –Phase IV trials may result in a drug being no longer sold (Harmful effects)

21 21 Design of Clinical Trials 1.Study objective 2.Study design 3.Sample size 4.Randomization 5.Allocation concealment 6.Blinding

22 22 Study objective Researcher and statistician should jointly articulate the objective of the study. The objective should be clearly defined. Ex: While drug “X” was testing for hypertension, the bald head patients reported hair growth. (Minoxidil) In the above situation, the researcher and statistician may get confusion while collecting the data

23 23 Study design Descriptive studies –Case reports –Case series –Population studies Analytical studies –Survey –Observational –Experimental

24 24 Descriptive Studies Case report –A method designed to give a detailed description of a single case Case series –A method designed to give a detailed description of more than one case Population studies –This is the observation of a defined population at a single point in time or time interval. Exposure and outcome are determined simultaneously.

25 25 Descriptive Studies: Uses Health care planning –Education or prevention and allocating resources more efficiently. Hypothesis generation –Searching for determinants or risk factors that can be altered or eliminated to reduce or prevent disease. Trend Analysis –Suggesting associations

26 26 Analytical studies Survey –It involves measuring a set of parameters in a population group or in a sample of subjects. –It is usually performed with a carefully developed and pre tested QUESTIONNAIRE. –Most effective for estimation of the frequency of parameters

27 27 Analytical studies Observational Studies –Cross-sectional –Case-control –Cohort

28 28 Analytical studies Observational Studies –Cross-sectional Data collected at a single point in time Describes associations Prevalence A “Snapshot”

29 29 Analytical studies Observational Studies – Case-Control Study Start with people who have disease Match them with controls that do not Look back and assess exposures

30 30 Analytical studies Observational Studies – Cohort Study Begin with disease-free patients Classify patients as exposed/unexposed Record outcomes in both groups Compare outcomes using relative risk

31 31 Analytical studies Experiment design –Simple experiment design –Parallel group design –Repeated measures design. –Crossover designs –Factorial design

32 32 Analytical studies Experiment design –Simple experiment design Subjects assigned as two groups. Treatment group & Control (or placebo) group. Treatment assigned to treatment group and no treatment or placebo assigned to control group. The outcome measures are compared at the end of experiment.

33 33 Analytical studies Experiment design –Parallel group design * A homogenous group of subjects is selected then subjects are randomly allocated into treatment & control groups. Ex: Total population = male + female Then the male & female subjects were separated as individual/parallel groups. * Disadvantage: Inter-subject variation is not being correlated.

34 34 Parallel group A B C D

35 35 Analytical studies Experiment design – Repeated measures design * Same as the simple experiment, but the repeated measures were taken in both, the treatment group as well as the control group. * Here the results are some more accurate than simple experiments.

36 36 Analytical studies Experiment design – Crossover design * Get two or more treatments successively. * Time gap - “WASH OUT PERIOD”. * This method minimizes the “inter-subject variation”; some more accurate than simple experiments. * Requires less no. of subjects to get meaningful results. * But the only disadvantage is, increased no. of study periods leads to subject drop outs & longer duration.

37 37 Analytical studies Experiment design – Factorial design * To estimate the effect of main treatment & other factors simultaneously. * In a specific case of 2 treatments A & B, * The groups taken as: Given neither A (A=0) nor B (B=0) Given A alone (A=1) & not B (B=0) Given B alone (B=1) & not A(A=0) Given both A (A=1) & B (B=1) DRUG B A Level B=1 B=0 A=0A=1 NoneA alone B aloneA&B both

38 38 Sample Size If few subjects were chosen, it may not give accurate outcome / the results are not trusty. If large no. of subjects were taken, then the time span and cost of the study will increases highly. But “Unfortunately there is no way of guaranteeing an adequate sample size”. The experienced investigator can only make an educated guess about the suitable adequate sample size.

39 39 Sample Size How to guess –Study objectives and hypothesis –Type I error and Type II error –Precision analysis –Power analysis

40 40 Randomization The probability that allows every subject to get equal treatment. To minimize or avoid bias and errors. Randomization techniques: –Simple randomization –blocked randomization –Stratified randomization –Factorial randomization

41 41 Randomization Simple randomization – Like “different color balls drawn from a basket”. –First the subjects satisfying selection criteria are identified. –Later, from the above group subjects are chosen in random manner.

42 42 Group.A Group.B SIMPLE RANDOMIZATION

43 43 Randomization Blocked randomization –number of subjects in one group versus the other group are specified, and subjects are allocated randomly within each block..

44 44 Randomization Stratified randomization –First all the subjects are divided into 2 specific groups (STRATA) on the basis of some predefined factor. So, 2 or more “Stratas” will formed. –Later, from the individual strata, the random samples will be taken& assigned as study groups.

45 STRATIFIED RANDOMIZATION Group.A Group.B MALE-STRATA FEMALE STRATA

46 46 Randomization Factorial randomization Ex: Comparison of response pattern with two treatments in depressed as well as non depressed male and female subjects. Randomize subjects from each type. Male – Depressed Male – Non depressed Female – Depressed Female – Non depressed

47 FACTORIAL RANDOMIZATIO FACTORS MALE SEX DEPRESSED NON DEPRESSED FEMALE DISEASESTATEDISEASESTATE A B

48 48 Allocation concealment Protecting the randomization process so that the treatment to be allocated is not known before the patient is entered into the study –seque Blinding –ntially-numbered –opaque – sealed envelopes (SNOSE) – sequentially-numbered containers – pharmacy controlled randomization – central randomization

49 49 Blinding Types of studies on the basis of blinding: –Open/ No blinding: Investigator, patient & statistician all are aware of treatment –Single blind One party, either the patient or the investigator aware of treatment. (Mostly the investigator will be aware.) –Double blind :Neither the investigator nor the patient are aware of treatment. –Triple blind Investigator, subject and the statistician is also not aware of treatment

50 50 Blinding Methods of achieving double blinding: –If two treatments are available in the form of tablets then matching both tablets in terms of colour/shape/size. – If two treatments available in different forms like tablet(A) & capsule(B), then all subjects are given both 1tablet & 1capsule. Here subjects assigned to treatment “A” will get original drug containing tablet and a placebo capsule. Subjects assigned to treatment “B” will get original drug containing capsule and a placebo tablet.

51 51 QUERIES????

52 52 Thank You!


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